Project Summary/Abstract This proposal describes a five-year training program for Dr. Kari Ekenstedt, a veterinarian and researcher in Comparative Medical Genetics at Purdue University. Her research uses the dog as a model to ascertain susceptibility genes for spinal abnormalities. She already has identified causal mutations for rare spinal disorders in ?short spine? dogs (i.e., spondylocostal dysostosis) and is now investigating the much more common phenotype of idiopathic scoliosis. Dr. Ekenstedt's co- primary mentors are Dr. Cathy Carlson at the University of Minnesota (UMN) (Professor and Department Chair, veterinarian, board certified pathologist, and NIH-funded researcher) and Dr. Gert Breur (Professor and director of Purdue's Center for Comparative Translational Research). Both co-primary mentors have extensive experience in musculoskeletal system research, pediatric orthopedic diseases, and skeletal development. Dr. Ekenstedt's other two mentors, Dr. Molly McCue at UMN and Dr. Peristera Paschou at Purdue, together have extensive mammalian genetics and genomics experience. This team will provide high caliber mentoring to enable Dr. Ekenstedt to become a productive, independent research professor. The K01 project will allow Dr. Ekenstedt to learn techniques that will enhance her future research potential, provide new directions to pursue in scoliosis research, and will result in multiple important publications. Dr. Ekenstedt will also train in grant writing and utilize these skills to procure independent funding. Idiopathic Scoliosis (IS) is a significant health problem affecting up to 3% of children globally. Very little is known about the pathophysiology of IS, and although there is a substantial inherited component to IS, susceptibility genes have largely evaded identification. Furthermore, the majority of animal models for scoliosis research are induced. Dogs, however, offer a naturally- occurring model of IS that has not yet been explored genetically and is not yet well-recognized as a natural IS model. The proposed project will study the genomes of dogs with multiple spinal abnormalities. The first objective is to investigate, via genome-wide association study, Pugs with thoracic hemivertebrae and, separately, Pugs with arachnoid fibrosis. The second objective is to investigate, via selective sweep analysis, Pugs, Basenjis, Bulldogs, and French Bulldogs for the fixed trait of ?screw-tail?, or wedge-shaped caudal (coccygeal) vertebrae. The third and final objective is to identify putative functional alleles for each of these abnormalities via whole- genome sequencing. By providing insight into the genetics of canine scoliosis conditions, this project will highlight genes for investigation of this disease in humans. The establishment of the genetic canine scoliosis model has great potential to lead to future therapeutic intervention trials.